Chlorhexidine, nalidixic acid and phosphanilic acid are known in the art. Moreover, as shown in U.S. Pat. Nos. 3,960,745, issued June 1, 1976, and 3,855,140, issued Dec. 17, 1974, certain chlorhexidine salts are likewise known. Such salts include the hydrochloride, gluconate, isethionate, formate, acetate, glutamate, succinamate, monodiglycolate, dimethanesulphonate, lactate, di-isobutyrate and the glucoheptonate.
Polyhydroxycarboxylic acid salts of biguanides, such as, for example, chlorhexidine di-D-gluconate, are disclosed in U.S. Pat. No. 2,990,425, issued June 27, 1961, as being highly soluble in water.
The oral antibacterial use of water soluble salts of chlorhexidine, such as the gluconate, acetate, fluoride, dihydrogen fluoride and the dihydrogen chloride, is disclosed in U.S. Pat. No. 3,976,765, issued Aug. 24, 1976.
An oral antibacterial composition comprising a combination of dodecyl-di-(aminoethyl)glycine and chlorhexidine or its digluconate, diacetate, dichloride or monofluorophosphate salts is disclosed in U.S. Pat. No. 3,932,607, issued Jan. 13, 1976.
Salts of chlorhexidine with certain sequestering amino carboxylic acids are disclosed in U.S. Pat. No. 3,888,947, issued June 10, 1975. Preferred salts include, mono-chlorhexidine nitrilotriacetate, trichlorhexidine, di-[diethylene triaminepentaacetate], mono-chlorhexidine-di-[N,N-dihydroxyethylaminoacetate], mono-chlorhexidine N-hydroxyethylenediaminetriacetate and mono-chlorhexidine di-[N-hydroxyethylethylenediaminetriacetate]. Such sequestrates are disclosed to have greater antibacterial activity than the corresponding bisguanido salt (confer column 3, lines 22 through 42 of the patent).
Bis-guanide hydroxyalkane sulphonic acid salts are disclosed in British Patent Specification No. 815,800. Such salts (including the isethionic acid salt, the 2:3-dihydroxypropane-1-sulphonic acid salt, the 3-chloro-2-hydroxypropane-1-sulphonic acid salt and the 2-hydroxypropane-1-sulphonic acid salt) are asserted to advantageously possess high solubility in water.
U.S. Pat. No. 3,252,181, issued Oct. 6, 1964, discloses monobiguanides having at least one alkoxypropyl group having from about 11 to 19 carbon atoms attached to the N.sup.1 or N.sup.5 terminal nitrogen atoms. Such compounds are said to display exceptional antimicrobial activity and may be employed as the free base or, where water solubility is a factor in their use, as their salts with the inorganic and organic acids (such as mono and polycarboxylic and sulfur-containing mono and poly acids and acidic nitrogen compounds). Exemplary of acid salts are the hydrochloride, hydrobromide, sulfate, phosphate, borate, phosphite, sulfite, sulfonate, nitrite, carbonate, nitrate, acetate, tartrate, propionate, oxalate, maleate, malate, picrate and .beta.-ethoxypropionate salts. Examples of suitable acidic nitrogen compounds are theophylline, substituted theophyllines and similar purines, saccharin, phthalimide, benzoxazine-2,4-diones, oxazolidine-2,4-dione and substituted oxazolidone-2,4-diones, N-p-methylbenzene sulfonyl-N'-n-butylurea, barbituric acids, mercaptobenzothiazole, 8-chlorotheophylline and succinimide. Patentees teach (at column 11, lines 36 through 70) that their monobiguanides can be employed with other medicaments.
As stated heretofore, nalidixic acid, phosphanilic acid and chlorhexidine are known in the art. The antibacterial agent, nalidixic acid (1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8 -naphthyridine-3-carboxylic acid) is the subject of U.S. Pat. No. 3,590,036, issued June 29, 1971. Nalidixic acid has not to the instant inventors' knowledge been heretofore utilized topically.
Phosphanilic acid (p--NH.sub.2 C.sub.6 H.sub.4 PO.sub.3 H.sub.2, 4-aminobenzene phosphonic acid) has been synthesized (inter alia Doak et al. JACS 74 (1952)) and found to be active against various organisms (see for example Kuhn et al., Ber. 75,711 (1942); Klotz et al., JACS 69,473 (1947); and Thayer et al., Antibiotics and Chemotherapy, 3,256 (1953)).
U.S. Pat. No. 3,159,537, issued Dec. 1, 1964, teaches that certain phosphonic acid compounds, including phosphanilic acid, increase the oral absorption (viz. increase blood level) of tetracycline antibiotics.
Complexes of phosphanilic acid and an aminoacridine compound (preferably, 9-amino, 3-amino or 6-amino acridine) are disclosed in U.S. Pat. Nos. 3,694,447, issued Sept. 26, 1972 and 3,794,723, issued Feb. 26, 1974, as having antibacterial and antifungal activity.
Phosphanilic acid has also been reported to show synergistic action with trimethoprim against a variety of bacteria (see U.S. Pat. No. 4,125,610, issued Nov. 14, 1978). It has also been reported to show synergistic action with neomycin and with streptomycin against Enterobacteriaceae (see Ciencia (Mexico) 17, 71-73 (1957)).
Finally, it should be noted that the topical anti-infective, chlorhexidine, (1,6-bis(N-p-chlorophenyldiguanido)hexane) is long known to the prior art having been disclosed in U.S. Pat. No. 2,684,924, issued July 27, 1954.